PD-1 Blockade Alone Versus in Combination With Chemotherapy as First Line Therapy in Females With Advanced NSCLC & PD-L1 Expression ≥50%

1\. Mixed histology including any small-cell component. Participants with mixed non-small cell histology (e.g., squamous and non-squamous) may be eligible only if the predominant component (≥50%) is squamous cell carcinoma or adenocarcinoma.

2\. Concurrent participation in another interventional clinical trial involving administration of an investigational medicinal product. Participation in non-interventional studies or registries is allowed.

3\. Prior systemic treatment for metastatic or locally advanced disease or prior PD-1/PD-L1 immunotherapies (including CD137 agonists or immune checkpoint inhibitors such as anti-CTLA-4, anti-TIGIT, anti-PD-1, or anti-PD-L1 antibodies).

4\. Concurrent radiotherapy for cancer treatment, except limited palliative radiotherapy for non-target lesions.

5\. Candidate for complete surgical removal of oligometastatic disease; participants refusing surgery/ablations may be included.

6\. Symptomatic or neurologically unstable CNS metastases or requiring increasing doses of steroids to manage CNS symptoms within 2 weeks prior to study entry (maximum acceptable dose: ≤10 mg prednisolone).

7\. Leptomeningeal disease. 8. History of interstitial lung disease. 9. Active infection requiring intravenous systemic therapy within 2 weeks prior to first study treatment. Participants with infections of CTCAE grade 1-2 that have been treated and clinically stabilized (e.g., uncomplicated urinary tract infection treated with oral antibiotics) may be included.

10\. Known additional malignancy other than NSCLC, either untreated or requiring active treatment within the past 3 years.

11\. Significant cardiovascular disease, including NYHA class ≥III congestive heart failure, clinically significant arrhythmias, or recent myocardial infarction (within 6 months). Left ventricular ejection fraction (LVEF) must be ≥50% (or ≥ institutional lower limit of normal) as assessed by echocardiogram or MUGA scan.

12\. Active autoimmune disease or history of autoimmune or chronic inflammatory disorders requiring systemic treatment (e.g., corticosteroids, immunosuppressants) within the past 2 years, including but not limited to celiac disease, systemic lupus erythematosus, sarcoidosis, Wegener's granulomatosis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis.

Note: Diverticulitis is considered under this criterion only if recurrent or chronic; uncomplicated diverticulosis is allowed.

Exceptions:

1. Vitiligo or alopecia

2. Hypothyroidism stable on hormone replacement

3. Controlled Type I diabetes mellitus on insulin

4. Chronic skin conditions not requiring systemic therapy

5. No active disease in the last 5 years (requires PI approval) 13. Current or prior use of immunosuppressive medication within 14 days before first pembrolizumab dose.

Exceptions:

1. Intranasal, inhaled, topical steroids, or local injections

2. Systemic corticosteroids at doses ≤10 mg/day prednisone equivalent

3. Steroids as premedication for hypersensitivity reactions 14. Treatment with systemic immunostimulatory agents (e.g., interferon, IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to study treatment.

15\. Live vaccine within 30 days prior to first dose of study treatment. 16. Known allergy or hypersensitivity to any component of the chemotherapy regimen or pembrolizumab.

17\. Any co-existing medical condition that, in the investigator's judgment, substantially increases risk associated with participation.

18\. Pregnant or breastfeeding women. 19. Participant incarcerated or involuntarily institutionalized by court order or authorities.

What this study is about